This invention relates generally to 4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones which are useful as inhibitors of HIV reverse transcriptase, pharmaceutical compositions and diagnostic kits comprising the same, methods of using the same for treating viral infection or as assay standards or reagents, and intermediates and processes for making the same.
Two distinct retroviruses, human immunodeficiency virus (HIV) type-1 (HIV-1) or type-2 (HIV-2), have been etiologically linked to the immunosuppressive disease, acquired immunodeficiency syndrome (AIDS). HIV seropositive individuals are initially asymptomatic but typically develop AIDS related complex (ARC) followed by AIDS. Affected individuals exhibit severe immunosuppression which predisposes them to debilitating and ultimately fatal opportunistic infections.
The disease AIDS is the end result of an HIV-1 or HIV-2 virus following its own complex life cycle. The virion life cycle begins with the virion attaching itself to the host human T-4 lymphocyte immune cell through the bonding of a glycoprotein on the surface of the virion""s protective coat with the CD4 glycoprotein on the lymphocyte cell. Once attached, the virion sheds its glycoprotein coat, penetrates into the membrane of the host cell, and uncoats its RNA. The virion enzyme, reverse transcriptase, directs the process of transcribing the RNA into single-stranded DNA. The viral RNA is degraded and a second DNA strand is created. The now double-stranded DNA is integrated into the human cell""s genes and those genes are used for virus reproduction.
At this point, RNA polymerase transcribes the integrated DNA into viral RNA. The viral RNA is translated into the precursor gag-pol fusion polyprotein. The polyprotein is then cleaved by the HIV protease enzyme to yield the mature viral proteins. Thus, HIV protease is responsible for regulating a cascade of cleavage events that lead to the virus particle""s maturing into a virus that is capable of full infectivity.
The typical human immune system response, killing the invading virion, is taxed because the virus infects and kills the immune system""s T cells. In addition, viral reverse transcriptase, the enzyme used in making a new virion particle, is not very specific, and causes transcription mistakes that result in continually changed glycoproteins on the surface of the viral protective coat. This lack of specificity decreases the immune system""s effectiveness because antibodies specifically produced against one glycoprotein may be useless against another, hence reducing the number of antibodies available to fight the virus. The virus continues to reproduce while the immune response system continues to weaken. Eventually, the HIV largely holds free reign over the body""s immune system, allowing opportunistic infections to set in and without the administration of antiviral agents, immunomodulators, or both, death may result.
There are at least three critical points in the virus""s life cycle which have been identified as possible targets for antiviral drugs: (1) the initial attachment of the virion to the T-4 lymphocyte or macrophage site, (2) the transcription of viral RNA to viral DNA (reverse transcriptase, RT), and (3) the processing of gag-pol protein by HIV protease.
Inhibition of the virus at the second critical point, the viral RNA to viral DNA transcription process, has provided a number of the current therapies used in treading AIDS. This transcription must occur for the virion to reproduce because the virion""s genes are encoded in RNA and the host cell reads only DNA. By introducing drugs that block the reverse transcriptase from completing the formation of viral DNA, HIV-1 replication can be stopped.
A number of compounds that interfere with viral replication have been developed to treat AIDS. For example, nucleoside analogs, such as 3xe2x80x2-azido-3xe2x80x2-deoxythymidine (AZT), 2xe2x80x2,3xe2x80x2-dideoxycytidine (ddC), 2xe2x80x2,3xe2x80x2-dideoxythymidinene (d4T), 2xe2x80x2,3xe2x80x2-dideoxyinosine (ddI), and 2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-thia-cytidine (3TC) have been shown to be relatively effective in halting HIV replication at the reverse transcriptase (RT) stage.
Non-nucleoside HIV reverse transcriptase inhibitors have also been discovered. As an example, it has been found that certain benzoxazinones are useful in the inhibition of HIV reverse transcriptase, the prevention or treatment of infection by HIV and the treatment of AIDS. U.S. Pat. No. 5,519,021, the contents of which are hereby incorporated herein by reference, describe reverse transcriptase inhibitors which are benzoxazinones of the formula: 
wherein X is a halogen, Z may be O. However, benzoxazinones of this type are specifically excluded from the present invention.
In U.S. Pat. No. 5,519,021 one compound in particular, (xe2x88x92) 6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (NNRTI), shown below, 
has been found to be a potent and specific inhibitor of HIV-1 reverse transcriptase worthy of further study. NNRTI is described in Step D of Example 6 of the disclosure. Rat, monkey, and human microsomes treated with NNRTI, during investigation of the cytochrome P450 metabolism of NNRTI, produced a metabolite which was discovered to also be a potent inhibitor of HIV reverse transcriptase. This metabolite, its stereoisomer, stereoisomeric mixtures, and derivatives thereof are an embodiment of the present invention.
Even with the current success of reverse transcriptase inhibitors, it has been found that HIV patients can become resistant to a single inhibitor. Thus, it is desirable to develop additional inhibitors to further combat HIV infection.
Accordingly, one object of the present invention is to provide novel reverse transcriptase inhibitors.
It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need thereof a therapeutically effective combination of (a) one of the compounds of the present invention and (b) one or more compounds selected form the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.
It is another object of the present invention to provide pharmaceutical compositions with reverse transcriptase inhibiting activity comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method of inhibiting HIV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of the present invention.
It is another object of the present invention to provide a kit or container containing at least one of the compounds of the present invention in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV reverse transcriptase, HIV growth, or both.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula (I): 
wherein A, W, X, Y, Z, R1 and R2 are defined below, stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salt forms thereof, are effective reverse transcriptase inhibitors.
[1] Thus, in a first embodiment, the present invention provides a novel compound of formula I: 
xe2x80x83or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
A is O or S;
W is N or CR3;
X is N or CR4;
Y is N or CR5;
Z is N or CR6;
provided that if two of W, X, Y, and Z are N, then the remaining are other than N;
also, provided that if X is CR4 and R4 is F, Cl, Br, or I, then:
(a) at least one of W, Y, and Z is other than CH;
(b) R2 is xe2x80x94OCHR7R8 or xe2x80x94NHCHR7R8;
(c) if R2 is Cxe2x89xa1Cxe2x80x94R8, then R8 is C3-7 cycloalkyl substituted with 1 R9; or
(d) any combination of (a), (b), and (c);
R1 is selected from CF3, CF2H, C2F5, C1-4 alkyl, C3-5 cycloalkyl, C2-4 alkenyl, and C2-4 alkynyl;
R2 is selected from xe2x80x94QCHR7R8, xe2x80x94QCHR7Cxe2x89xa1Cxe2x80x94R8, xe2x80x94QCHR7Cxe2x95x90Cxe2x80x94R8, xe2x80x94Q(CH2)pCHR7R8, xe2x80x94Cxe2x89xa1Cxe2x80x94R8, xe2x80x94CHxe2x95x90CR7R8, xe2x80x94(CH2)pCHR7R8, xe2x80x94CHR7Cxe2x89xa1Cxe2x80x94R8, xe2x80x94CHR7CHxe2x95x90CHR8, and CHxe2x95x90CHCHR7R8;
provided that when R1 is C1-4 alkyl, then R2 is xe2x80x94Cxe2x89xa1Cxe2x80x94R8;
R3 is selected from H, F, Cl, Br, I, C1-3 alkoxy, and C1-3 alkyl;
R4 is selected from H, F, Cl, Br, I, C1-3 alkyl substituted with 0-3 R11, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, OCF3, xe2x80x94CN, NO2, CHO, C(O)CH3, C(O)CF3, C(O)NH2, C(O)NHCH3, NR7R7a, NR7C(O)OR7a, C(O)OR7, S(O)pR7, SO2NHR7, NR7SO2R7b, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R10;
alternatively, R3 and R4 together form xe2x80x94OCH2Oxe2x80x94;
R5 is selected from H, F, Cl, Br, and I;
alternatively, R4 and R5 together form xe2x80x94OCH2Oxe2x80x94 or a fused benzo ring;
R6 is selected from H, OH, C1-3 alkoxy, xe2x80x94CN, F, Cl, Br, I, NO2, CF3, CHO, C1-3 alkyl, and C(O)NH2;
R7 is selected from H and C1-3 alkyl;
R7a is selected from H and C1-3 alkyl;
R7b is C1-3 alkyl;
R8 is selected from H, C1-6 alkyl substituted with 0-3 R11, CH(xe2x80x94OCH2CH2Oxe2x80x94), C2-6 alkenyl, C3-7 cycloalkyl substituted with 0-2 R9, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R10;
R9 is selected from D, OH, C1-3 alkoxy, C1-3 alkyl, and F;
R10 is selected from OH, C1-3 alkyl, C1-3 alkoxy, F, Cl, Br, I, CN, NR7R7a, and C(O)CH3;
R11 is selected from OR7, CN, F, Cl, Br, I, NO2, NR7R7a, CHO, C(O)CH3, C(O)NH2;
Q is selected from O, S and NH; and,
p is selected from 0, 1, and 2.
[2] In a preferred embodiment, the present invention provides a novel compound of formula I, wherein:
R1 is selected from CF3, CF2H, C2F5, C1-3 alkyl, C3-5 cycloalkyl; and,
R8 is selected from H, C1-6 alkyl substituted with 0-3 R11, CH(xe2x80x94OCH2CH2Oxe2x80x94), C2-6 alkenyl, C3-5 cycloalkyl substituted with 0-1 R9, phenyl substituted with 0-1 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R10.
[3] In a more preferred embodiment, the present invention provides a novel compound of formula I, wherein:
R1 is selected from CF3, CF2H, C2F5, C2H5, isopropyl, cyclopropyl;
R3 is selected from H, F, Cl, Br, I, OCH3, CH3;
R4 is selected from H, F, Cl, Br, I, C1-3 alkyl substituted with 0-3 R11, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, OCF3, xe2x80x94CN, NO2, CHO, C(O)CH3, C(O)CF3, C(O)NH2, C(O)NHCH3, NR7R7a, NR7C(O)OR7a, C(O)OR7, S(O)pR7, SO2NHR7, NR7SO2R7b, phenyl, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
alternatively, R3 and R4 together form xe2x80x94OCH2Oxe2x80x94;
R5 is selected from H, F;
R6 is selected from H, OH, OCH3, xe2x80x94CN, F, CF3, CH3, and C(O)NH2;
R7 is selected from H and CH3;
R7a is selected from H and CH3;
R7b is CH3;
R8 is selected from H, C1-4 alkyl substituted with 0-3 R11, CH(xe2x80x94OCH2CH2Oxe2x80x94), C2-4 alkenyl, C3-5 cycloalkyl substituted with 0-1 R9, phenyl substituted with 0-1 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R10;
R9 is selected from D, OH, OCH3, OH3, and F;
R10 is selected from OH, CH3, OCH3, F, Cl, Br, I, CN, NR7R7a, and C(O)CH3; and,
p is selected from 1 and 2.
[4] In an even more preferred embodiment, the present invention provides a novel compound of formula I, wherein:
A is O;
R1 is selected from CF3, CF2H, C2F5;
R2 is selected from xe2x80x94OCHR7R8, xe2x80x94OCH2Cxe2x89xa1Cxe2x80x94R8, xe2x80x94OCH2Cxe2x95x90Cxe2x80x94R8, xe2x80x94OCH2CHR7R8, xe2x80x94Cxe2x89xa1Cxe2x80x94R8, xe2x80x94CHxe2x95x90CR7R8, xe2x80x94CH2CHR7R8, xe2x80x94CH2Cxe2x89xa1Cxe2x80x94R8, CHR7CHxe2x95x90CHR8, and CHxe2x95x90CHCHR7R8;
R3 is selected from H, F, Cl, Br, I;
R4 is selected from H, F, Cl, Br, I, C1-3 alkyl substituted with 0-3 R11, CHxe2x95x90CH2, Cxe2x89xa1CH, OCH3, OCF3, xe2x80x94CN, NO2, CHO, C(O)CH3, C(O)CF3, C(O)NH2, C(O)NHCH3, NR7R7a, C(O)OR7, NR7SO2R7b, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
alternatively, R3 and R4 together form xe2x80x94OCH2Oxe2x80x94; and,
R11 is selected from OH, OCH3, CN, F, Cl, NR7R7a, C(O)CH3, and C(O)NH2.
[5] In a further preferred embodiment, the compound of the present invention is selected from:
(+/xe2x88x92)-6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;
(xe2x88x92)-6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;
(+/xe2x88x92)-6-Chloro-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;
(+/xe2x88x92)-4-Clopropylethynyl-4-isopropyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;
(+/xe2x88x92)-4-Isopropylethynyl-4-trifluoromethyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;
(+/xe2x88x92)-6-Acetyl-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;
(+/xe2x88x92)-5,6-Difluoro-4-(3-methyl)-1-buten-1-yl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;
(+/xe2x88x92)-4-Isopropylethynyl-4-trifluoromethyl-5,6-difluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one;
(+/xe2x88x92)-4-Cyclopropylethynyl-6-chloro-4-trifluoromethyl-7-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one;
(+/xe2x88x92)-6-Chloro-4-(2-methoxyethoxy)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;
(+/xe2x88x92)-6-Chloro-4-propylamino-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;
(+/xe2x88x92)-6-Chloro-4-(2-(furan-2-yl)ethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;
(+/xe2x88x92)-4-(1-Butynyl)-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;
(+/xe2x88x92)-4-(1xe2x80x2-Hydroxy)-cyclopropylethynyl-4-trifluoromethyl-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-one;
(+/xe2x88x92)-4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one;
(+/xe2x88x92)-6-Chloro-4-(1-deuterocycloprop-1-ylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; and,
(+/xe2x88x92)-4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one.
[6] In a second embodiment, the present invention provides a novel compound of formula II: 
xe2x80x83or a salt or stereoisomer thereof, wherein:
A is O or S;
W is N or CR3;
X is N or CR4;
Y is N or CR5;
Z is N or CR6;
provided that if two of W, X, Y, and Z are N, then the remaining are other than N;
R1a is selected from CF3, CF2H, C2F5, C1-4 alkyl, C3-5 cycloalkyl, C2-4 alkenyl, and C2-4 alkynyl;
R3 is selected from H, F, Cl, Br, I, C1-3 alkoxy, and C1-3 alkyl;
R4 is selected from H, F, Cl, Br, I, C1-3 alkyl substituted with 0-3 R11, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, OCF3, xe2x80x94CN, NO2, CHO, C(O)CH3, C(O)CF3, C(O)NH2, C(O)NHCH3, NR7R7a, NR7C(O)OR7a, C(O)OR7, S(O)pR7, SO2NHR7, NR7SO2R7b, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R10;
alternatively, R3 and R4 together form xe2x80x94OCH2Oxe2x80x94;
R5 is selected from H, F, Cl, Br, and I;
alternatively, R4 and R5 together form xe2x80x94OCH2Oxe2x80x94 or a fused benzo ring;
R6 is selected from H, OH, C1-3 alkoxy, xe2x80x94CN, F, Cl, Br, I, NO2, CF3, CHO, C1-3 alkyl, and C(O)NH2;
R7 is selected from H and C1-3 alkyl;
R7a is selected from H and C1-3 alkyl;
R7b is C1-3 alkyl;
R10 is selected from OH, C1-3 alkyl, C1-3 alkoxy, F, Cl, Br, I, CN, NR7R7a, and C(O)CH3;
R11 is selected from OR7, CN, F, Cl, Br, I, NO2, NR7R7a, CHO, C(O)CH3, C(O)NH2;
p is selected from 0, 1, and 2.
[7] In a another preferred embodiment, the present invention provides a novel compound of formula II, wherein:
A is O; and,
R1a is selected from CF3, CF2H, C2F5, C1-3 alkyl, C3-5 cycloalkyl.
[8] In a more preferred embodiment, the present invention provides a novel compound of formula II, wherein:
R1a is selected from CF3, CF2H, C2F5, C2H5, isopropyl, cyclopropyl;
R3 is selected from H, F, Cl, Br, I, OCH3, CH3;
R4 is selected from H, F, Cl, Br, I, C1-3 alkyl substituted with 0-3 R11, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, OCF3, xe2x80x94CN, NO2, CHO, C(O)CH3, C(O)CF3, C(O)NH2, C(O)NHCH3, NR7R7a, NR7C(O)OR7a, C(O)OR7, S(O)pR7, SO2NHR7, NR7SO2R7b, phenyl, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
alternatively, R3 and R4 together form xe2x80x94OCH2Oxe2x80x94;
R5 is selected from H, F;
R6 is selected from H, OH, OCH3, xe2x80x94CN, F, CF3, CH3, and C(O)NH2;
R7 is selected from H and CH3;
R7a is selected from H and CH3;
R7b is CH3;
R10 is selected from OH, CH3, OCH3, F, Cl, Br, I, CN, NR7R7a, and C(O)CH3; and,
p is selected from 1 and 2.
[9] In an even more preferred embodiment, the present invention provides a novel compound of formula II, wherein:
R1a is selected from CF3, CF2H, C2F5;
R3 is selected from H, F, Cl, Br, I;
R4 is selected from H, F, Cl, Br, I, C1-3 alkyl substituted with 0-3 R11, CHxe2x95x90CH2, Cxe2x89xa1CH, OCH3, OCF3, xe2x80x94CN, NO2, CHO, C(O)CH3, C(O)CF3, C(O)NH2, C(O)NHCH3, NR7R7a, C(O)OR7, NR7SO2R7b, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
alternatively, R3 and R4 together form xe2x80x94OCH2Oxe2x80x94; and,
R11 is selected from OH, OCH3, CN, F, Cl, NR7R7a, C(O)CH3, and C(O)NH2.
[10] In a third embodiment, the present invention provides a novel process for making a compound of formula II: 
xe2x80x83or a salt or stereoisomer thereof, comprising:
(a) contacting a compound of formula III: 
xe2x80x83or a suitable salt form thereof, with a carbonyl or thiocarbonyl delivering agent in the presence of a suitable solvent, wherein:
A is O or S;
W is N or CR3;
X is N or CR4;
Y is N or CR5;
Z is N or CR6;
provided that if two of W, X, Y, and Z are N, then the remaining are other than N;
R1a is selected from CF3, CF2H, C2F5, C1-4 alkyl, C3-5 cycloalkyl, C2-4 alkenyl, and C2-4 alkynyl;
R3 is selected from H, F, Cl, Br, I, C1-3 alkoxy, and C1-3 alkyl;
R4 is selected from H, F, Cl, Br, I, C1-3 alkyl substituted with 0-3 R11, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, OCF3, xe2x80x94CN, NO2, CHO, C(O)CH3, C(O)CF3, C(O)NH2, C(O)NHCH3, NR7R7a, NR7C(O)OR7a, C(O)OR7, S(O)pR7, SO2NHR7, NR7SO2R7b, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R10;
alternatively, R3 and R4 together form xe2x80x94OCH2xe2x80x94;
R5 is selected from H, F, Cl, Br, and I;
alternatively, R4 and R5 together form xe2x80x94OCH2Oxe2x80x94 or a fused benzo ring;
R6 is selected from H, OH, C1-3 alkoxy, xe2x80x94CN, F, Cl, Br, I, NO2, CF3, CHO, C1-3 alkyl, and C(O)NH2;
R7 is selected from H and C1-3 alkyl;
R7a is selected from H and C1-3 alkyl;
R7b is C1-3 alkyl;
R10 is selected from OH, C1-3 alkyl, C1-3 alkoxy, F, Cl, Br, I, CN, NR7R7a, and C(O) CH3;
R11 is selected from OR7, CN, F, Cl, Br, I, NO2, NR7R7a, CHO, C(O)CH3, C(O)NH2;
Q is selected from O, S and NH; and,
p is selected from 0, 1, and 2.
[11] In another preferred embodiment, in formulae II and III,
A is O;
R1a is selected from CF3, CF2H, C2F5;
R3 is selected from H, F, Cl, Br, I;
R4 is selected from H, F, Cl, Br, I, C1-3 alkyl substituted with 0-3 R11, CHxe2x95x90CH2, Cxe2x89xa1CH, OCH3, OCF3, xe2x80x94CN, NO2, CHO, C(O)CH3, C(O)CF3, C(O)NH2, C(O)NHCH3, NR7R7a, C(O)OR7, NR7SO2R7b, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
alternatively, R3 and R4 together form xe2x80x94OCH2Oxe2x80x94; and,
R5 is selected from H, F;
R6 is selected from H, OH, OCH3, xe2x80x94CN, F, CF3, CH3, and C(O)NH2;
R7 is selected from H and CH3;
R7a is selected from H and CH3;
R7b is CH3;
R10 is selected from OH, CH3, OCH3, F, Cl, Br, I, CN, NR7R7a, and C(O)CH3;
R11 is selected from OH, OCH3, CN, F, Cl, NR7R7a, C(O)CH3, and C(O)NH2; and,
p is selected from 1 and 2.
[12] In another more preferred embodiment, the carbonyl delivering agent is selected from phosgene, carbonyldiimidazole, chloromethylcarbonate, chloroethylcarbonate, dimethylcarbonate, diethylcarbonate, and di-t-butylcarbonate.
[13] In another even more preferred embodiment, the carbonyl delivering agent is phosgene and the solvent is toluene.
[14] In another more preferred embodiment, in step (a) a base is present and is selected from trimethylamine, triethylamine, and N,N-disopropylethylamine.
[15] In a fourth embodiment, the present invention provides of process for making a compound of formula Ia: 
xe2x80x83or a stereoisomer or pharmaceutically acceptable salt form thereof, comprising:
(a) contacting a nucleophile, R2b, with a compound of formula II: 
xe2x80x83or stereoisomer thereof in a suitable solvent, wherein:
R2b is selected from R8R7CHxe2x80x94OH, R8R7CHxe2x80x94OM, R8R7CHNH2, R8R7CHNHxe2x80x94M, R8xe2x80x94Cxe2x89xa1Cxe2x80x94M, R7R8Cxe2x95x90CHxe2x80x94M, R8R7CH(CH2)pxe2x80x94M, R8CHxe2x95x90CHC(H)(R7)xe2x80x94M, R8R7CHCHxe2x95x90CHxe2x80x94M;
M is selected from Na, Li, Mg, Zn, Cu, Pd, Pt, Sn, Al, and B;
A is O or S;
W is N or CR3;
X is N or CR4;
Y is N or CR5;
Z is N or CR6;
provided that if two of W, X, Y, and Z are N, then the remaining are other than N;
R1a is selected from CF3, CH2H, C2F5, C1-4 alkyl C3-5 cycloalkyl, C2-4 alkenyl, and C2-4 alkynyl;
R2a is selected from xe2x80x94QCHR7R8, xe2x80x94QCHR7Cxe2x89xa1Cxe2x80x94R8, xe2x80x94QCHR7Cxe2x95x90Cxe2x80x94R8, xe2x80x94Q(CH2)pCHR7R8, xe2x80x94Cxe2x89xa1Cxe2x80x94R8, xe2x80x94CHxe2x95x90CR7R8, xe2x80x94(CH2)pCHR7R8, xe2x80x94CHR7Cxe2x89xa1Cxe2x80x94R8, xe2x80x94CHR7CHxe2x95x90CHR8, and CHxe2x95x90CHCHR7R8;
R3 is selected from H, F, Cl, Br, I, C1-3 alkoxy, and C1-3 alkyl;
R4 is selected from H, F, Cl, Br, I, C1-3 alkyl substituted with 0-3 R11, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, OCF3, xe2x80x94CN, NO2, CHO, C(O)CH3, C(O)CF3, C(O)NH2, C(O)NHCH3, NR7R7a, NR7C(O)OR7a, C(O)OR7, S(O)pR7, SO2NHR7, NR7SO2R7b, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R10;
alternatively, R3 and R4 together form xe2x80x94OCH2Oxe2x80x94;
R5 is selected from H, F, Cl, Br, and I;
alternatively, R4 and R5 together form xe2x80x94OCH2Oxe2x80x94 or a fused benzo ring;
R6 is selected from H, OH, C1-3 alkoxy, xe2x80x94CN, F, Cl, Br, I, NO2, CF3, CHO, C1-3 alkyl, and C(O)NH2;
R7 is selected from H and C1-3 alkyl;
R7a is selected from H and C1-3 alkyl;
R7b is C1-3 alkyl;
R8 is selected from H, C1-6 alkyl substituted with 0-3 R11, CH(xe2x80x94OCH2CH2Oxe2x80x94), C2-6 alkenyl, C3-7 cycloalkyl substituted with 0-2 R9, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R10;
R9 is selected from D, OH, C1-3 alkoxy, C1-3 alkyl, and F;
R10 is selected from OH, C1-3 alkyl, C1-3 alkoxy, F, Cl, Br, I, CN, NR7R7a, and C(O)CH3;
R11 is selected from OR7, CN, F, Cl, Br, I, NO2, NR7R7a, CHO, C(O)CH3, C(O)NH2;
Q is selected from O, S and NH; and,
p is selected from 0, 1, and 2.
[16] In another preferred embodiment, in formulae Ia and II,
A is O;
R1a is selected from CF3, CF2H, C2F5;
R2a is selected from xe2x80x94OCHR7R8, xe2x80x94OCH2Cxe2x89xa1Cxe2x80x94R8, xe2x80x94OCH2Cxe2x95x90Cxe2x80x94R8, xe2x80x94OCH2CHR7R8, xe2x80x94Cxe2x89xa1Cxe2x80x94R8, xe2x80x94CHxe2x95x90CR7R8, xe2x80x94CH2CHR7R8, xe2x80x94CH2Cxe2x89xa1Cxe2x80x94R8, CHR7CHxe2x95x90CHR8, and CHxe2x95x90CHCHR7R8;
R3 is selected from H, F, Cl, Br, I;
R4 is selected from H, F, Cl, Br, I, C1-3 alkyl substituted with 0-3 R11, CHxe2x95x90CH2, Cxe2x89xa1CH, OCH3, OCF3, xe2x80x94CN, NO2, CHO, C(O)CH3, C(O)CF3, C(O)NH2, C(O)NHCH3, NR7R7a, C(O)OR7, NR7SO2R7b, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
alternatively, R3 and R4 together form xe2x80x94OCH2Oxe2x80x94; and,
R5 is selected from H, F;
R6 is selected from H, OH, OCH3, xe2x80x94CN, F, CF3, CH3, and C(O)NH2;
R7 is selected from H and CH3;
R7a is selected from H and CH3;
R7b is CH3;
R8 is selected from H, C1-4 alkyl substituted with 0-3 R11, CH(xe2x80x94OCH2CH2Oxe2x80x94), C2-4 alkenyl, C3-5 cycloalkyl substituted with 0-1 R9, phenyl substituted with 0-1 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R10;
R9 is selected from D, OH, OCH3, CH3, and F;
R10 is selected from OH, CH3, OCH3, F, Cl, Br, I, CN, NR7R7a, and C(O)CH3;
R11 is selected from OH, OCH3, CN, F, Cl, NR7R7a, C(O)CH3, and C(O)NH2; and,
p is selected from 1 and 2.
[17] In another more preferred embodiment, in step (a), the compound of formula II is added to a solution containing the nucleophile.
[18] In another more preferred embodiment, in step (a), R2b is R8xe2x80x94Cxe2x89xa1Cxe2x80x94M; and M is selected from Li, Mg, and Zn.
[19] In another even more preferred embodiment, in step (a), R8xe2x80x94Cxe2x89xa1Cxe2x80x94M is formed in situ by addition of a strong base to a solution containing R8xe2x80x94Cxe2x89xa1Cxe2x80x94H.
[20] In another further preferred embodiment, in step (a), the strong base is selected from n-butyl lithium, s-butyl lithium, t-butyl lithium, phenyl lithium, and methyl lithium.
[21] In another further preferred embodiment, the compound of formula Ia is: 
xe2x80x83the compound of formula Ia is: 
xe2x80x83the nucleophile R2b is lithium cyclopropylacetylide; and, the solvent is THF.
[22] In a fifth embodiment, the present invention provides a novel method of making a compound of formula IIIb: 
xe2x80x83or stereoisomer or salt form thereof, comprising:
(a) contacting a compound of formula IIIa: 
xe2x80x83with R1a-TMS and an anion, wherein:
the anion is a fluoride or oxyanion and is selected from tetrabutylammonium fluoride, sodium fluoride, potassium fluoride, lithium fluoride, cesium fluoride, potassium tert-butoxide, sodium methoxide, sodium ethoxide and sodium trimethylsilanolate;
Pg is an amine protecting group;
W is N or CR3;
X is N or CR4;
Y is N or CR5;
Z is N or CR6;
provided that if two of W, X, Y, and Z are N, then the remaining are other than N;
R1a is selected from CF3, CF3CF2, and CF3CF2CF2;
R3 is selected from H, F, Cl, Br, I, C1-3 alkoxy, and C1-3 alkyl;
R4 is selected from H, F, Cl, Br, I, C13 alkyl substituted with 0-3 R11, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, OCF3, xe2x80x94CN, NO2, CHO, C(O)CH3, C(O)CF3, C(O)NH2, C(O)NHCH3, NR7R7a, NR7C(O)OR7a, C(O)OR7, S(O)pR7, SO2NHR7, NR7SO2R7b, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R10;
alternatively, R3 and R4 together form xe2x80x94OCH2Oxe2x80x94;
R5 is selected from H, F, Cl, Br, and I;
alternatively, R4 and R5 together form xe2x80x94OCH2Oxe2x80x94 or a fused benzo ring;
R6 is selected from H, OH, C1-3 alkoxy, xe2x80x94CN, F, Cl, Br, I, NO2, CF3, CHO, C1-3 alkyl, and C(O)NH2;
R7 is selected from H and C1-3 alkyl;
R7a is selected from H and C1-3 alkyl;
R7b is C1-3 alkyl;
R10 is selected from OH, C1-3 alkyl, C1-3 alkoxy, F, Cl, Br, I, CN, NR7R7a, and C(O)CH3;
R11 is selected from OR7, CN, F, Cl, Br, I, NO2, NR7R7a, CHO, C(O)CH3, C(O)NH2;
p is selected from 0, 1, and 2.
[23] In another preferred embodiment, in formulae IIIa and IIIb,
the R1a-TMS is trifluoromethyl trimethylsilane;
the anion is tetrabutylammonium fluoride;
Pg is trityl;
R1a is CF3;
R3 is selected from H, F, Cl, Br, I;
R4 is selected from H, F, Cl, Br, I, C1-3 alkyl substituted with 0-3 R11, CHxe2x95x90CH2, Cxe2x89xa1CH, OCH3, OCF3, xe2x80x94CN, NO2, CHO, C(O)CH3, C(O)CF3, C(O)NH2, C(O)NHCH3, NR7R7a, C(O)OR7, NR7SO2R7b, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
alternatively, R3 and R4 together form xe2x80x94OCH2Oxe2x80x94; and,
R5 is selected from H, F;
R6 is selected from H, OH, OCH3, xe2x80x94CN, F, CF3, CH3, and C(O)NH2;
R7 is selected from H and CH3;
R7a is selected from H and CH3;
R7b is CH3;
R10 is selected from OH, CH3, OCH3, F, Cl, Br, I, CN, NR7R7a, and C(O)CH3;
R11 is selected from OH, OCH3, CN, F, Cl, NR7R7a, C(O)CH3, and C(O)NH2; and,
p is selected from 1 and 2.
[24] In another more preferred embodiment, the process further comprises:
(b) contacting a compound of formula IIIb with an oxidizing agent to form compound of formula IIIc: 
[25] In another even more preferred embodiment, the oxidizing agent is MnO2.
In a fifth embodiment, the present invention provides a novel pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I or pharmaceutically acceptable salt form thereof.
In a sixth embodiment, the present invention provides a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of formula I or pharmaceutically acceptable salt form thereof.
In a seventh embodiment, the present invention provides a novel method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of:
(a) a compound of formula I; and,
(b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.
In another preferred embodiment, the reverse transcriptase inhibitor is a nucleoside reverse transcriptase inhibitor.
In another more preferred embodiment, the nucleoside reverse transcriptase inhibitor is selected from AZT, 3TC, rescriptor, ddI, ddC, and d4T and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, VX-478, nelfinavir, KNI-272, CGP-61755, and U-103017.
In an even more preferred embodiment, the nucleoside reverse transcriptase inhibitor is selected from AZT, rescriptor, and 3TC and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, and nelfinavir.
In a still further preferred ebodiment, the nucleoside reverse transcriptase inhibitor is AZT.
In another still further preferred embodiment, the protease inhibitor is indinavir.
In a eighth embodiment, the present invention provides a pharmaceutical kit useful for the treatment of HIV infection, which comprises a therapeutically effective amount of:
(a) a compound of formula I; and,
(b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors, in one or more sterile containers.
In a ninth embodiment, the present invention provides a novel method of inhibiting HIV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of formula I.
In a tenth embodiment, the present invention to provides a novel a kit or container comprising a compound of formula (I) in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV reverse transcriptase, HIV growth, or both.
As used herein, the following terms and expressions have the indicated meanings. It will be appreciated that the compounds of the present invention contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
The processes of the present invention are contemplated to be practiced on at least a multigram scale, kilogram scale, multikilogram scale, or industrial scale. Multigram scale, as used herein, is preferably the scale wherein at least one starting material is present in 10 grams or more, more preferably at least 50 grams or more, even more preferably at least 100 grams or more. Multikilogram scale, as used herein, is intended to mean the scale wherein more than one kilogram of at least one starting material is used. Industrial scale as used herein is intended to mean a scale which is other than a laboratory scale and which is sufficient to supply product sufficient for either clinical tests or distribution to consumers.
The reactions of the synthetic methods claimed herein may be, as noted herein, carried out in the presence of a suitable base, said suitable base being any of a variety of bases, the presence of which in the reaction facilitates the synthesis of the desired product. Suitable bases may be selected by one of skill in the art of organic synthesis. Suitable bases include, but are not intended to be limited to, inorganic bases such as alkali metal, alkali earth metal, thallium, and ammonium hydroxides, alkoxides, phosphates, and carbonates, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, thallium hydroxide, thallium carbonate, tetra-n-butylammonium carbonate, and ammonium hydroxide. Suitable bases also include organic bases, including but not limited to aromatic and aliphatic amines, such as pyridine; trialkyl amines such as triethylamine, N,N-diisopropylethylamine, N,N-diethylcyclohexylamine, N,N-dimethylcyclohexylamine, N,N,Nxe2x80x2-triethylenediamine, N,N-dimethyloctylamine; 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); 1,4-diazabicyclo[2.2.2]octane (DABCO); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); tetramethylethylenediamine (TMEDA); and substituted pyridines such as N,N-dimethylaminopyridine (DMAP), 4-pyrrolidinopyridine, 4-piperidinopyridine.
Suitable halogenated solvents include: carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane, tetrachloroethylene, trichloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane, 2-chloropropane, hexafluorobenzene, 1,2,4-trichlorobenzene, o-dichlorobenzene, chlorobenzene, or fluorobenzene.
Suitable ether solvents include, but are not intended to be limited to, dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, or t-butyl methyl ether.
Suitable protic solvents may include, by way of example and without limitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, anisole, benzyl alcohol, phenol, or glycerol.
Suitable aprotic solvents may include, by way of example and without limitation, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMAC), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, or hexamethylphosphoramide.
Suitable hydrocarbon solvents include, but are not intended to be limited to, benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, or naphthalene.
As used herein, the term xe2x80x9camine protecting groupxe2x80x9d (or xe2x80x9cN-protectedxe2x80x9d) refers to any group known in the art of organic synthesis for the protection of amine groups. As used herein, the term xe2x80x9camine protecting group reagentxe2x80x9d refers to any reagent known in the art of organic synthesis for the protection of amine groups which may be reacted with an amine to provide an amine protected with an amine protecting group. Such amine protecting groups include those listed in Greene and Wuts, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d John Wiley and Sons, New York (1991) and xe2x80x9cThe Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference. Examples of amine protecting groups include, but are not limited to, the following: 1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl (trityl) and benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl.
Amine protecting groups may include, but are not limited to the following: 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothio-xanthyl)]methyloxycarbonyl; 2-trimethylsilylethyloxycarbonyl; 2-phenylethyloxycarbonyl; 1,1-dimethyl-2,2-dibromoethyloxycarbonyl; 1-methyl-1-(4-biphenylyl)ethyloxycarbonyl; benzyloxycarbonyl; p-nitrobenzyloxycarbonyl; 2-(p-toluenesulfonyl)ethyloxycarbonyl; m-chloro-p-acyloxybenzyloxycarbonyl; 5-benzyisoxazolylmethyloxycarbonyl; p-(dihydroxyboryl)benzyloxycarbonyl; m-nitrophenyloxycarbonyl; o-nitrobenzyloxycarbonyl; 3,5-dimethoxybenzyloxycarbonyl; 3,4-dimethoxy-6-nitrobenzyloxycarbonyl; Nxe2x80x2-p-toluenesulfonylaminocarbonyl; t-amyloxycarbonyl; p-decyloxybenzyloxycarbonyl; diisopropylmethyloxycarbonyl; 2,2-dimethoxycarbonylvinyloxycarbonyl; di(2-pyridyl)methyloxycarbonyl; 2-furanylmethyloxycarbonyl; phthalimide; dithiasuccinimide; 2,5-dimethylpyrrole; benzyl; 5-dibenzylsuberyl; triphenylmethyl; benzylidene; diphenylmethylene; or methanesulfonamide.
As used herein, xe2x80x9calkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFwwhere v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. xe2x80x9cAlkoxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. xe2x80x9cAlkenylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like. xe2x80x9cAlkynylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo and iodo. xe2x80x9cCounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like.
As used herein, xe2x80x9carylxe2x80x9d or xe2x80x9caromatic residuexe2x80x9d is intended to mean an aromatic moiety containing the specified number of carbon atoms, such as phenyl or naphthyl. As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3- to 7-membered monocyclic or bicyclic which may be saturated, partially unsaturated, or aromatic. Examples of such carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic systemxe2x80x9d is intended to mean a stable 5- to 6-membered monocyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 3 heteroatoms independently selected from the group consisting of N, O and S. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d is intended to mean a stable 5- to 6-membered monocyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 3 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, 2-pyrrolidonyl, 2H-pyrrolyl, 4-piperidonyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, isoxazolyl, morpholinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl., oxazolyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrahydrofuranyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, and oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
As used herein, xe2x80x9cHIV reverse transcriptase inhibitorxe2x80x9d is intended to refer to both nucleoside and non-nucleoside inhibitors of HIV reverse transcriptase (RT). Examples of nucleoside RT inhibitors include, but are not limited to, AZT, ddC, ddI, d4T, and 3TC. Examples of non-nucleoside RT inhibitors include, but are not limited to, rescriptor (delavirdine, Pharmacia and Upjohn), viviradine (Pharmacia and Upjohn U90152S), TIBO derivatives, BI-RG-587, nevirapine, L-697,661, LY 73497, and Ro 18,893 (Roche).
As used herein, xe2x80x9cHIV protease inhibitorxe2x80x9d is intended to refer to compounds which inhibit HIV protease. Examples include, but are not limited, saquinavir (Roche, Ro31-8959), ritonavir (Abbott, ABT-538), indinavir (Merck, MK-639), VX-478 (Vertex/Glaxo Wellcome), nelfinavir (Agouron, AG-1343), KNI-272 (Japan Energy), CGP-61755 (Ciba-Geigy), and U-103017 (Pharmacia and Upjohn). Additional examples include the cyclic protease inhibitors disclosed in WO93/07128, WO 94/19329, WO 94/22840, and PCT Application Number US96/03426.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) or other formulas or compounds of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of the present invention, for example formula (I), are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein the hydroxy or amino group is bonded to any group that, when the prodrug is administered to a mammalian subject, cleaves to form a free hydroxyl or free amino, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention, and the like. xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Only stable compounds are contempleted by the present invention.
xe2x80x9cSubstitutedxe2x80x9d is intended to indicate that one or more hydrogens on the atom indicated in the expression using xe2x80x9csubstitutedxe2x80x9d is replaced with a selection from the indicated group(s), provided that the indicated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O) group, then 2 hydrogens on the atom are replaced.
xe2x80x9cTherapeutically effective amountxe2x80x9d is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit HIV infection or treat the symptoms of HIV infection in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of HIV replication) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Each of the references cited below are hereby incorporated herein by reference. 
Scheme 1 illustrates a method of making 4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones starting from an appropriately substituted 2-aminobenzoic acid. The acid is converted to its N-methoxy-N-methyl amide derivative which can then be displaced to obtain the R1-substituted ketone. Subsequent addition of another metallic species provides the alcohol which is readily cyclized with phosgene or an equivalent thereof. 
Scheme 2 describes a means of obtaining 4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-ones starting from an appropriately substituted aniline. After iodination, the trifluoromethyl group can be introduced using a strong base and ethyl trifluoroacetate. The second 4-substituent can then be added through anion attack on the ketone or using other means well known to those of skill in the art. Cyclization can be then be completed as in Scheme 1. 
Because certain benzo-substituents are incompatible with the methods of Schemes 1 and 2, it may be necessary to protect these groups before forming the benzoxazinone. In Scheme 3 there is shown a means of obtaining carbonyl-substituted 4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones. After iodination of an acetyl-aniline, the acetyl group is protected by means well known to those of skill in the art, such as using 1,3-propanedithiol. The same procedures as in Scheme 2 are used to arrive at the cyclized product. Deprotection of the ketone can then be achieved using HgCl2 and HgO or other means well known to those of skill in the art. 
A method for forming 4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones, wherein R2 is a vinyl or alkynyl group, is described in Scheme 4. Starting from an appropriately substituted ketone which can be obtained using the procedure of Scheme 1 or 2, an acetylide is added. The product can be deprotected and cyclized to obtain the alkynyl-substituted material. Alternatively, the vinyl compounds can be obtained by reduction of the alkyne with a reducing agent, such as LiAlH4, deprotection by standard means, and cyclization. 
Scheme 5 describes an alternate route to 4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones from anilines, wherein the aniline is protected, ester addition is accomplished using a strong base and the amine protecting group is removed. The R2 group can then be added, e.g. via an acetylide, followed by cyclization. 
An intermediate useful in the preparation of the presently claimed compounds is 2-trifluoroacetylaniline. The starting 4-chloro-2-trifluoroacetylaniline can be made as shown in Scheme 2. Reduction and reoxidation removes the chloro group leaving the desired intermediate. 
Scheme 7A describes a novel method of making 2-trifluoroacetylanilines as well as how these compounds can be further modified to make the presently claimed compounds. The protected aldehyde can be made from the N-methoxy-N-methyl amide of Scheme 1, by addition of a protecting group, preferably trityl, and reduction of the amide to the aldehyde. Other protecting groups known to those of skill in the art can be used in place of the shown trityl group. 
Scheme 7B illustrates specific steps of Scheme 7A. Intermediate IIIb (R1a is selected from CF3, CF3CF2, and CF3CF2CF2) is useful for making some of the presently claimed compounds. Pg is an amine protecting group as defined previously, preferably trityl (triphenylmethyl). The protected or unprotected aminobenzaldehyde, preferably protected, is treated with a perfluoralkyl trimethylsilane, preferably trifluoromethyl trimethylsilane, followed by fluoride anion, preferably tetrabutylammonium fluoride. In the same fashion, CF3CF2TMS, CF3CF2CF2TMS can also be used to prepare the appropriately substituted ketones. Other sources of fluoride anion such as sodium fluoride, potassium fluoride, lithium fluoride, cesium fluoride as well as oxyanionic species such as potassium tert-butoxide, sodium methoxide, sodium ethoxide and sodium trimethylsilanolate can also be used. Aprotic solvents such as DMF and THF can be used, preferably THF. The amount of perfluoralkyl trimethylsilane used can be from about 1 to about 3 equivalents with an equivalent amount of fluoride anion or oxyanionic species. The reaction can be typically carried out at temperatures between about xe2x88x9220xc2x0 C. to about 50xc2x0 C., preferably about xe2x88x9210 to about 10xc2x0 C., more preferably about 0xc2x0 C.
Conversion of IIIb to IIIc can be achieved by using an oxidizing agent well known to one of skill in the art such as MnO2, PDC, PCC, K2Cr2O7, CrO3, KMnO4, BaMNO4, Pb(OAc)4, and RuO4. A preferred oxidant is MnO2. Such conversion can be performed in an aprotic solvent like THF, DMF, dichloromethane dichloroethane, or tetrachloroethane, preferably dichloromethane. 
Scheme 8 illustrates a method of forming aza-4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones from an appropriately substituted amino-pyridine. Carbonyl addition to the pyridine can be accomplished using a strong base and an appropriate ketone. Addition of base can afford the cyclized product. 
An additional means of making 4-alkynyl-1,4-dihydro-2H-3,1-benzoxazin-2-ones is shown in Scheme 9. The alkyne group is added to the keto-aniline via a Grignard type addition, followed by cyclization. The alkyne group of the product can then be modified to obtain the desired compound. 
In addition to the methods of obtaining keto-anilines described in Schemes 1 and 2, nucleophilic opening of isatoic anhydrides can also be used as shown in Scheme 10. This reaction is accomplished by using an anionic nucleophile of the group R1a. See Mack et al, J. Heterocyclic Chem. 1987, 24, 1733-1739; Coppola et al, J. Org. Chem. 1976, 41(6), 825-831; Takimoto et al, Fukuoka Univ. Sci. Reports 1985, 15(1), 37-38; Kadin et al, Synthesis 1977, 500-501; Staiger et al, J. Org. Chem. 1959, 24, 1214-1219.
It is preferred that the stoichiometry of the isatoic anhydride reagent to nucleophile is about 1.0 to 2.1 molar equivalents. The use of 1.0 eq. or more (e.g., 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0) of anion (or anion precursor) is preferred to force the conversion and improve the isolated yield. Preferably, the temperature used is from xe2x88x9220 to +35xc2x0 C., with temperatures below 0xc2x0 C. being more preferred and xe2x88x9220xc2x0 C. being even more preferred. Reactions are run to about completion with time dependent upon inter alia nucleophile, solvent, and temperature. Preferably this nucleophilic addition is run in THF, but any aprotic solvent would be suitable. Reaction with the active nucleophilic anion is the only criterion for exclusion of a solvent. 
An intermediate in this novel process is the chlorobenzoxazinone (II) which can be synthesized from the corresponding keto-aniline as shown in Scheme 11. The preparation of compounds of formula II works well with either the free base of the keto-aniline or its hydrochloride hydrate, though the free base is preferred due to its inherent reactivity. The carbonylation or thiocarbonylation reagent is selected from the group: phosgene (COCl2), thiophosgene (CSCl2), carbonyldiimidazole (CDI), chloromethylcarbonate, chloroethylcarbonate, dimethylcarbonate, diethylcarbonate, and di-t-butylcarbonate. Preferably, phosgene is used as the carbonylation reagent.
About 1, 2, 3, 4, or 5 equivalents of carbonylation or thiocarbonylation reagent are used, preferably from about 1 to about 2.5, even more preferably from about 1 to 2, and still further preferably about 1, 1.1, 1.2, 1.3, 1.4, or 1.5 equivalents. With volatile reagents like phosgene more than one equivalent can help the conversion and yield of the reaction but is not necessary to effect transformation.
Solvents such as toluene may be used. Additional non-reactive solvents, such as ethers (e.g., dimethyl ether and diethyl ether), hydrocarbons (e.g., hexane and cyclohexane) or other aromatic solvents (e.g., benzene, anisole, or quinoline) can also be used. Solvents with boiling points around that of toluene or higher are preferred. Use of such solvents allows heat to be applied to the reaction to promote the cyclization. When the preferred carbonylation reagent, phosgene is use, heat helps drive off the HCl generated and promote the closure reaction. When toluene is used, it is preferred to run the reaction near toluene""s boiling point. However, one of ordinary skill in the art would recognize that too high of a temperature may decompose the product. In addition, too low of a temperature may cause an undesirably slow reaction. Reaction progress may be determined by the decoloration of the reaction mixture (indicating consumption of starting material) and confirmation of completeness by proton NMR. The reaction may be catalyzed by the addition of an acid scavenger such as an amine base (e.g., triethylamine or Hunigs base) or an inorganic base (e.g., sodium carbonate or potassium). 
Scheme 12 describes routes to a variety of R2-substituted compounds of formula Ia by reacting a nucleophile (R2b) with a compound of formula II (preferably R1a is CF3). This displacement reaction is quite versatile and a large range of nucleophiles can be used. Preferably the nucleophile is an amine (e.g., R8R7CHNH) or a metallic species selected from R8R7CHxe2x80x94OM, R8R7CHxe2x80x94SM, R8R7CHNHxe2x80x94M, R8xe2x80x94Cxe2x89xa1Cxe2x80x94M, R7R8Cxe2x95x90CHxe2x80x94M, R8R7CH(CH2)pxe2x80x94M, R8CHxe2x95x90CHC(H)(R7) xe2x80x94M, and R8R7CHCHxe2x95x90CHxe2x80x94M. In addition, R8R7CHxe2x80x94OH and its thiol analog, R8R7CHxe2x80x94SH, can be used without formation of their corresponding anions. The metallic moiety, M, is selected from the group Na, Li, Zn, Mg, Cu, Pd, Pt, Sn, Al, and B, preferably Li, Mg, or Zn.
If an metallic nucleophile is used, it may be made in situ by methods known to those of skill in the art or formed by methods known to those of skill in the art and then added to a solution. In either case, it is preferred that the compound of formula II is added to a solution containing the nucleophile.
Preferably, the nucleophile is an acetylide (i.e., R8xe2x80x94Cxe2x89xa1Cxe2x80x94M) with Li, Mg, or Zn as the counterion. Acetylides are well known in the art. Preferably, R8xe2x80x94Cxe2x89xa1Cxe2x80x94M is formed in situ by addition of a strong base to a solution containing R8xe2x80x94Cxe2x89xa1Cxe2x80x94H. Strong bases are well known to those of skill in the art and include, but are not limited to n-butyl lithium, s-butyl lithium, t-butyl lithium, phenyl lithium, and methyl lithium. Preferably, the strong base is n-butyl lithium. The acetylide may also be made in situ by addition of a strong base to a dihalo-olefin (e.g., Br2Cxe2x95x90CHR8).
In the nucleophilic addition reactions the stochiometery is preferably about one equivalent of benzoxazinone to about 1.0 to 2.5 equivalents of nucleophile (e.g., 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, or 2.5). More preferable about 1.8 to 2.4 equivalents are used. Even more preferably, 2.1 equivalents of nucleophile are used. It is noted that less than one equivalent may be used, but care must be taken as Nxe2x80x94H deprotonation reaction may compete with nucleophilic addition. It is preferable to run the additions from xe2x88x9240 to 0xc2x0 C., more preferably about xe2x88x9220xc2x0 C. The solvent used is preferably THF, but any aprotic solvent, such as dimethyl ether, diethyl ether, benzene, or toluene, should be suitable. Non-reaction with the nucleophile, specifically the nucleophilic anion, is the only criterion for exclusion of a solvent.
An additional example of the utility of the final nucleophilic addition step of the present invention is shown in Scheme 13. 
A preferred example of the present process is shown in Scheme 14. 
In Scheme 14, the preferred temperature of the carbonylation reaction is from about 104 to about 110xc2x0 C. and the preferred temperature of the acetylide addition is about xe2x88x9220xc2x0 C.
One enantiomer of a compound of Formula I may display superior activity compared with the other. Thus, both of the following stereochemistries are considered to be a part of the present invention. 
When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Steven D. Young, et al, Antimicrobial Agents and Chemotheraphy, 1995, 2602-2605. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g. Andrew S. Thompson, et al, Tet. lett. 1995,36, 8937-8940.
Another method of forming a compound wherein Z is C(OH) involves incubating NNRTI, or a derivative thereof, in microsomes obtained from male rats, male rhesus monkeys or humans, preferably male rats. In addition, it is preferable to orally dose the male rats with NNRTI prior to collection of their livers and microsomal isolation. This procedure will be described in the following Example section.